There are number of pharmaceutical drugs that are poorly soluble or insoluble in aqueous solutions. Such drugs provide challenges in terms of having poor oral bioavailability or in terms of formulating them for drug delivery especially through the intravenous route. If a drug is intravenously administered, particles must be small enough to safely pass through capillaries without causing emboli. For intravenous administration, it is recognized as safe to administer drugs in the form of solution, emulsion, liposomes, nanodispersions and the like. Another requirement that should be met while formulating a drug delivery system especially for hydrophobic drugs is that the formulation should be physically stable with no substantial aggregation or crystallization of the drug or change in appearance of the formulation on storage at room temperature for desired period of time.
Certain drugs exhibit very poor solubility in water and in most pharmaceutically acceptable solvents thus limiting their administration to patients. For example, commercially available product is Torisel® injection which comprises temsirolimus and dehydrated alcohol (39.5% w/v), dl-alpha-tocopherol (0.075% w/v), propylene glycol (50.3% w/v), and anhydrous citric acid (0.0025% w/v), polysorbate 80 (40.0% w/v). After the TORISEL (temsirolimus) injection vial has been diluted with diluent the solution contains 35.2% alcohol. Yet another injectable available in the market comprising high amount of surfactant is Sandimmune® Injection (cyclosporine injection, USP) available in a 5 mL sterile ampoule for I.V. administration. Each mL contains: cyclosporine, USP 50 mg; *Cremophor® EL (polyoxyethylated castor oil) 650 mg; alcohol, Ph. Helv 32.9% by volume which must be diluted further with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use. Cremophor EL, a polyoxyethylated castor oil vehicle, and dehydrated ethanol USP (1:1, v/v) are used. Although these solvents systems are biologically and pharmacologically acceptable, they have known to have side effects, including acute hypersensitivity reactions and peripheral neuropathies. It may be noted that the use of solubilizers like Cremophor™ EL in large amounts lead to various adverse effects such as serious or fatal hypersensitive and hypertensive reactions, bradyarrhythmia, anemia, neutropenia and/or peripheral neuropathy.
WO2008127358A2 (hereafter referred to as '358 patent publication) discloses aqueous solutions for water insoluble drugs, with the use of phospholipid included in a lipid complex. The proportion of at least one phospholipid is between about 5% to about 98% of a final lipid complex (e.g., a commercially usable form) by weight. In general, the amount of at least one phospholipid is between 10% to 90% by weight of the lipid complex. In contrast, the composition of the present invention utilizes optionally phospholipids that too in very small amounts. It was found surprisingly, that the composition comprising water insoluble drugs such as the polyene antibiotics, tacrolimus, sirolimus could be effectively solubilized without the use of large amounts of phospholipids as taught by '358 patent publication.
Another prior art, namely, PCT publication WO 2008144355 A2 discloses a stable oral liquid fenofibrate formulations that include a fenofibrate component and a pharmaceutically acceptable liquid carrier that is present in an amount sufficient to solubilize the fenofibrate and that includes a lipophilic component, a surfactant component, at least one monohydric alcohol, and optionally in some embodiments an aqueous component, wherein the formulation is substantially free of an oily phase. Also included are stable liquid fenofibrate formulations including a prophylactically or therapeutically effective amount of fenofibrate and a liquid carrier present in less than 5 ml that is sufficient to maintain dissolution of the fenofibrate under ambient temperature. It may be important to note that although the formulation disclosed herein are free of oily phase, the publication teaches that the formulation can contains a lipophilic component comprising at least one triglyceride of one or more fractionated vegetable fatty acids including C to C10; a surfactant component wherein the surfactant has a HLB value of greater than 10 in amounts as high as 30 percent to about 70 percent, preferably from about 42.5 percent to about 65 percent and/or from about 46 percent to about 57.5 percent. The presence of such high amounts of surfactant may not be desirable for the above reasons discussed.
United States patent application US20040005339 (Patent application '339) claims a pharmaceutical formulation of a fibrate with improved oral bioavailability comprising a fibrate selected from fenofibrate, derivative of fenofibrate or mixtures thereof dissolved in a water miscible fibrate solubilizer selected from N-alkyl derivative of 2-pyrrolidone, ethylene glycol monoether, C8-12 fatty acid ester of polyethylene glycol, fatty acids and combinations thereof; wherein the fibrate to solubilizer weight ratio is between about 1:1 and about 1:100. We have found out a formulation that solubilizers the fenofibrate with an amount of surfactants that is lower than the amount of fenofibrate.
In view of these problems associated with marketed formulations having very high amount of surfactants or high amounts of phospholipids, we have developed a composition that is using very, very low amounts of surfactant. We have developed a nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a water miscible solvent and water, said nanoparticles comprising a drug, a polymer and very low amount of surfactants and further is substantially free of phospholipids. Also the present inventors have found that molecules like fenofibrate which present lot of problems of dissolution and therefore poor bioavailability, were successfully formulated to achieve desirable dissolution when the drugs like fenofibrate were incorporated into the nanodispersion vehicle of the present invention. This results was unexpected because dissolution behaviour of drugs like fenofibrate is absolutely unpredictable.